Atherosclerotic diseases are the leading cause of mortality in Veteran population. Macrophages are the most prominent cell type in atherosclerotic lesions. The lipid-laden macrophages (foam cells) formation and subsequent inflammation in the arterial wall are the major pathogenesis for development of the diseases. Nuclear receptors have been reported to play a critical role in the lipid metabolism and inflammatory response. However, the regulation of their activity is unclear. It has been shown that there are major perturbations in cholesterol metabolism. The potential mechanisms by which such perturbations may lead to atherosclerosis via nuclear receptor signaling remain unclear. This knowledge gap in the field is a major barrier towards understanding the role of cholesterol metabolites in the pathogenesis of atherosclerosis and leveraging this information to develop novel therapies for atherosclerosis. We hypothesize that decreased SULT2B1b activity with consequent decreases in its metabolic product 25HC3S promotes atherosclerosis by (1) dysinhibition of the pro- lipogenic transcriptional factor, sterol response element binding protein-1c (SREBP-1c), due to failure to inactivate oxysterol signaling; and (2) disability of suppressing of inflammatory responses by decreasing IkB levels. These dysfunctions are caused by failure to regulate nuclear liver receptor homologue-1 (LRH-1). We will test the hypothesis by the following specific aims: 1). To explore that decreased SULT2B1b activity with consequent decreases in its metabolic product 25HC3S promotes atherosclerosis in vitro in free fatty acid-induced and in vivo high fat diet-induced atherosclerotc models. 2). To test potential of overexpression of SULT2B1b and administration 25HC3S to prevent/reverse lipid accumulation in blood and aortic wall in animal models. 3) To elucidate the molecular mechanism by which 25HC3S regulates LRH-1 activity: its role in lipid metabolism and inflammatory responses. These will provide a sufficient scientific background for development of new therapeutic strategies. The successful completion of the proposed studies will positively impact the field by: 1) providing a novel mechanism for the development of atherosclerosis, 2) identifying novel therapeutic targets for the treatment of atherosclerosis, and (3) opening new avenues of research focusing on the role of disordered cholesterol metabolism in the genesis and progression of atherosclerotic diseases.